Studies On Galactose-modified PEG-PLA/TPGS Micelles For Oral Delivery Of Curcumin

Curcumin is a diketone compound extracted from the rhizome of some plants of the zingiberaceae and araceae.Medical research showed that curcumin has the functions of lowering blood lipid,anti-tumor,anti-inflammation,promoting gallbladder and anti-oxidation.However,curcumin still has some defects,such as low solubility,poor stability,low absorption rate,easy transformation into compounds such as glutaraldehyde and sulfonic acid in the intestinal tract,fast metabolism and short half-life.The existence of these problems leads to low bioavailability and limits the application in the field of medicine.Polymer micelles are self-assembled nano-carriers with core-shell structure driven by amphiphilic polymers through hydrophobic action.The hydrophobic segment in the polymer aggregates to form a hydrophobic core,which can be used to contain insoluble drugs.The hydrophilic segment forms a hydrophilic shell in the outer layer to play a space protection role.In addition,by coupling the corresponding ligand on the carrier material,the targeted function of the micelle can be realized and the residence time of the drug in the special absorption site can be increased,which has been widely studied.Polyethylene glycol-polylactic acid(PEG-PLA)is an amphiphilic block copolymer with good biocompatibility and biodegradability.PEG with chemical modification groups can be used to connect specific ligands and play a targeted role through the ligand-receptor binding mechanism.In this study,galactose modified(Gal-PEG-PLA)and polyethylene glycol 1000 vitamin E succinate(TPGS)were used as carrier materials to construct a targeted oral micelle preparation.Gal-PEG-PLA was synthesized by amide reaction,and its successful synthesis was confirmed by 1H-NMR and IR spectra.Gal-PEG-PLA/TPGS oral micellar preparations with low,medium and high galactose contents were denoted as GPP1,GPP2 and GPP3,respectively.They were prepared by thin film dispersion method and their physicochemical properties were investigated.The release of CUR-GPP1,CUR-GPP2 and CUR-GPP3 oral micelles in simulated gastric fluid(SGF),simulated intestinal fluid(SIF)and pH 7.4 PBS was investigated by dialysis method.The results showed that the release of the micelles in vitro had sustained release characteristics,which was beneficial to the continuous release of micelles in the gastrointestinal tract.MTT assay was used to evaluate the cytotoxicity of Gal-PEG-PLA/TPGS oral micelles in Caco-2 cells.The results showed that micellar materials had no toxicity to caco-2 cells and good safety.The Gal-PEG-PLA/TPGS micelles uptake by caco-2 cells was observed by fluorescence microscopy.The results showed that Gal-PEG-PLA/TPGS micelles could be successfully absorbed by Caco-2 cells,and the uptake increased with the increase of galactose concentration.Caco-2 monolayers study results showed that CUR-GPP3 group significantly promoted the transport of CUR in normal intestinal epithelial cells.The UV spectrophotometric method for the determination of curcumin in intestinal circulation was established.The permeability of CUR-PP,CUR-GPP1,CUR-GPP2 and CUR-GPP3 in different intestinal segments of rats was studied.The results showed that CUR-GPP3 group significantly increased the permeability of curcumin in jejunum and ileum.The distribution of GPP1,GPP2 and GPP3 oral micellar in intestinal segment of rat was studied by in vivo NIRF imaging.The results showed that compared with other groups,GPP3 oral micelles remained in the intestinal tract for longer and more GPP3 remained in the intestinal tract,which was conducive to the full absorption and transportation of the oral micelles in the intestinal tract.The results of confocal laser scanning microscopy(CLSM)showed that GPP3 oral micelles could significantly improve the uptake of jejunum and ileum.HPLC method for determination of curcumin in rat plasma was established.The in vivo pharmacokinetic results showed that after the encapsulation of curcumin by Gal-PEG-PLA/TPGS micelles,the maximum plasma concentration and the area under the drug time curve were significantly increased,and the absorption of curcumin in the gastrointestinal tract was promoted.